OBJECTIVES
Treatment of Venous Thrombosis and Treatment of Venous Thrombosis and Pulmonary Embolism Pulmonary Embolism
• Prevent death from PE
• Prevent post-thrombotic syndrome
• Prevent recurrent venous thromboembolism (VTE)
• Achieve these objectives with minimal side effects and inconvenience
Treatment of VTETreatment of VTE
• Anticoagulants
• Thrombolytic therapy
• Caval interruption
• Surgical removal
AnticoagulantsAnticoagulants• Initial treatment with heparin is necessary.• Induction period with heparin therapy can be
reduced to 5 days.• Treatment following hospital discharge is necessary.• LMWH is a major advance.• Optimal therapeutic range with warfarin established.• Optimal duration of warfarin therapy still to be established.• New oral small-molecule direct thrombin inhibitor.*
* Does not have FDA approval for any indication.
Thrombolytic TherapyThrombolytic Therapy
• Not often indicated in venous thrombosis
• Useful in major PE
• Possible new indication in PE
Caval FilterCaval Filter
• A single randomized trial has defined advantages and drawbacks of caval filters. The results indicate that inferior venacaval filters:
a) Prevent recurrent PE in short term
b) Increase the risk of recurrent deep venousthrombosis (DVT) in the long term
SurgerySurgery
• Endarterectomy for chronic thromboembolic pulmonary hypertension can be life saving.
• Venous surgery is rarely indicated.
• Venous stenting combined with catheter-directed thrombolytic therapy is being used in some centers to treat patients with iliofemoral venous thrombosis and severe obstruction.
AnticoagulantsAnticoagulants
• Heparin
• Vitamin K antagonists (warfarin)
• LMWH
• Danaparoid*
• Hirudin*
• Pentasaccharide*
• Oral small-molecule direct thrombin inhibitor**Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.
Oral: Multiple clinical trials Small molecule DTI†*
Injection: Phase 3Pentasaccharide*
InjectionHirudin*
InjectionDanaparoid*
OralWarfarin
InjectionLMWH
Injection Heparin
*Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.
†DTI=direct thrombin inhibitor
AnticoagulantsAnticoagulants
TF VII
IX
XaX
IXa
a
II Va
IIa
VIIIa
FIBRINOGEN FIBRIN
Coagulation CascadeCoagulation Cascade
TF VII
IX
XaX
IXa
a
II Va
IIa
VIIIa
FIBRINOGEN FIBRIN
WARF
WARF
WARF
WARF
UFH, LMWHUFH, LMWH
UFH, LMWH
Established AnticoagulantsEstablished Anticoagulants
TF VIIa
IX
XaX
IXa
II Va
IIa
VIIIa
FIBRINOGEN FIBRIN
New AnticoagulantsNew Anticoagulants
PENTASAC*HIRUDIN*
ORAL SMALL- MOLECULE DTI †*
†
* Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.
† DTI=direct thrombin inhibitor
New Anticoagulants for Treatment of DVTNew Anticoagulants for Treatment of DVT
• Hirudin* (recombinant; lepirudin) is effective for treating thrombosis associated with HIT.
• The new oral small-molecule direct thrombin inhibitor* appears promising in multiple clinical trials.
• Pentasaccharide* has been evaluated in phase 2 studies and is being tested in phase 3 studies.
* Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT.The new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.
• Initial treatment with heparin is necessary.• Induction period with heparin therapy can be
reduced to 5 days. • LMWH can replace heparin and is now treatment
of choice.• Continued treatment following hospital discharge
is necessary.• Optimal therapeutic range with warfarin is an INR
of 2.0 to 3.0.• Optimal duration of warfarin therapy still to
be established.
Established AnticoagulantsEstablished Anticoagulants
Initial Treatment With Heparin Necessary Initial Treatment With Heparin Necessary in Treating Proximal Vein Thrombosisin Treating Proximal Vein Thrombosis
ConfirmedSymptomaticRecurrence
Positive
Negative
Total
Placebo and Acenocoumarol
12
48
60
Heparin and Acenocoumarol
4
56
60
Group Total
16
104
120
P = 0.058
Data from Brandjes et al, 1992
Confirmed Symptomatic Recurrence and/or Confirmed Symptomatic Recurrence and/or Venographic Evidence of Significant Extension Venographic Evidence of Significant Extension
and/or New High-Probability V/Q Scanand/or New High-Probability V/Q Scan
Positive
Negative
Total
Placebo and Acenocoumarol
28
25
53
Heparin and Acenocoumarol
7
42
49
Group Total
35
67
102
P < 0.001
Data from Brandjes et al, 1992
Event
Induction Period With Heparin Induction Period With Heparin Can Be Reduced to 5 DaysCan Be Reduced to 5 Days
Recurrent VTE
During heparin
During warfarin
Total duringtreatment
Short(4 days)
3.6%
3.3%
6.9%
Long(9.5 days)
4.7%
1.6%
6.3%
Short(5 days)
0%
7.1%
7.1%
Long(10 days)
0%
7.0%
7.0%
Gallus 1986 (266 pts) Hull 1990 (199 pts)
Treatment Following Hospital Treatment Following Hospital Discharge NecessaryDischarge Necessary
Author RecurrentVTE (%)
Lagerstedt 0
29
VTE = venous thromboembolism; SC = subcutaneous
Initial Courseof Heparin
5 days
Long-TermTreatment
Hull 0
47
14 days Warfarinvs
SC heparin 5000twice daily
Warfarinvs
no treatment
Hull et al, 1979; Lagerstedt et al, 1985
LMWH: A Major AdvanceLMWH: A Major Advance• Weight-adjusted subcutaneous dosing predictable
(Handeland et al,1990; Bratt et al, 1990)• Mechanism of more predictable dose response
(Young et al, 1993, 1994)• Less osteopenia than UFH (Shaughnessy et al, 1995; Monreal et al,
1994)• Less HIT than UFH (Warkentin et al, 1995)• Once-daily subcutaneous dosing effective in DVT (Hull et al, 1992)• Outpatient treatment effective and safe (Levine et al, 1996; Koopman
et al, 1996)• Treatment of PE effective and safe (Columbus Investigators, 1997;
Simonneau et al, 1997)
Meta-AnalysisMeta-AnalysisLMWH vs Heparin for Treatment of DVTLMWH vs Heparin for Treatment of DVT
Primary Studies:
Duroux, 1991Hull, 1992Prandoni, 1992Lopaciuk, 1992
Levine, 1996Koopman, 1996Fiessinger, 1996Luomanmaki, 1996Columbus, 1997
All studies (fixed-effect model)
Simonneau, 1993Lindmarker, 1994
Gould et al, 1999
Recurrent Thromboembolism(n=3566)
OR 0.85(P=0.28)
0.01 0.1 1 10 100FavorsLMWH
FavorsUFHOdds Ratio (OR)
Efficacy and Safety of Two Trials Using Efficacy and Safety of Two Trials Using Outpatient LMWHOutpatient LMWH
Study
Levine
Koopman
Treatment
UFH
UFH
LMWH
LMWH
Number
253
198
247
202
RecurrentVTE
6.7%
8.6%
5.3%
6.9%
MajorBleeding
1.2%
2.0%
2.0%
0.5%
Hospital
6.5
Days in
1.1
8.12.7
Levine et al, 1996; Koopman et al, 1996
A Comparison of LMWH (Tinzaparin) A Comparison of LMWH (Tinzaparin) With UFH for the Treatment of Acute PEWith UFH for the Treatment of Acute PE
Outcome Event IV Heparin SC LMWH 175 U/kg QD
Simonneau et al, 1997
Days 1–8 3 414 (4.5%) 12 (3.9%)
Death
Days 1–90
Days 1– 8 2 36 (1.9%) 5 (1.6%)
Recurrent TE
Days 1–90
Days 1–8 5 38 (2.6%) 6 (2.0%)
Major bleeding
Days 1–90
Days 1–8 9 (2.8%) 9 (3.0%)22 (7.1%) 18 (5.9%)
Composite
Days 1–90
n = 308 n = 304
IV=intravenous; SC=subcutaneous; QD=once daily; TE=thrombotic events
Harrison et al, 1998
Treatment of DVT in PracticeTreatment of DVT in Practice• Two hospitals, 1 year• 113 consecutive patients referred to thrombosis units• 13 excluded (no local treatment [5], outpatient UFH [8])• 11 hospitalized
– Comorbid disease (4)– High risk of bleeding (3)– Pain control (1)– Inadequate home support (1)– Weekend admission (2)
• 89 received outpatient LMWH– 75% self-injected or had family member perform injections.
Harrison et al, 1998
OutcomesOutcomesRecurrent VTE 7% (6/89)• Fatal PE and bleed (1)• DVT (5); all had cancer
Major Bleeding 2% (2/89)• Fatal bleed and PE (1)• Arm bleed: hospitalized
Patient Satisfaction Very: 91% (75/82)
• Dosing in obese patients and in renal insufficiency
• Dosing in pregnancy
• Protamine reversal
• Interchangeability of different preparations
LMWH: Outstanding QuestionsLMWH: Outstanding Questions
Trial of Intensive versus Less Intensive Trial of Intensive versus Less Intensive Warfarin Therapy (3 Months)Warfarin Therapy (3 Months)
Regimen
INR 3.0–4.0
INR 2.0–3.0
Frequency ofRecurrent VTE
2%
2%
Frequency ofBleeding
Complications
22%
4%
Hull et al, 1982
Warfarin
StudyNo. of
Patients
%AnnualizedRecurrence
No. ofPatients
%AnnualizedRecurrence
Prandoni et al, 1996 145 19 105 4
BTS, 1992 596 13 116 3
Hirsh, 1995 117 15 70 1
Levine et al, 1995 212 16 89 0
Schulman et al, 1995 553 9 344 3.5
IDIOPATHIC DVT* POSTOP DVT
* Idiopathic and continuing risk factorsBTS = British Thoracic Society
Risk Factors for RecurrenceRisk Factors for Recurrence
Study
Schulman et al, 1995
Rate of Recurrence After DiscontinuingRate of Recurrence After DiscontinuingAnticoagulants in PatientsAnticoagulants in Patients
With Idiopathic ThrombosisWith Idiopathic Thrombosis
Kearon et al, 1999
Months ofObservation
24
10
No. ofPatients
553
83
%AnnualizedRecurrence
9
27
Recurrent VTE
Major bleeding
Warfarin versus Placebo After Initial Warfarin versus Placebo After Initial 3 Months of Warfarin Therapy for 3 Months of Warfarin Therapy for
First Idiopathic VTEFirst Idiopathic VTE
Placebo(n=83)
17 (27%/patient-year)
0 (0%/patient-year)
Warfarin(n=79)
1 (1.3%/patient-year)
3 (3.8%/patient-year)
Prespecified interim efficacy analysis led to termination afteran average of 10 months.
Kearon et al, 1999
Risk Factors for Recurrence in Patients Risk Factors for Recurrence in Patients With Idiopathic VTE Treated With With Idiopathic VTE Treated With
Warfarin for 3 MonthsWarfarin for 3 Months
All patients
Antiphospholipidantibody
Factor V Leiden
Prothrombinmutation
Hazard Ratio
4.0(1.2–13)
0.5
2.2
Kearon et al, 1999
No Recurrence
49/66 (74)
2/61 (3)
17/59 (29)
2/59 (3)
No./Total No. (%)Recurrent VTE
17/66 (26)
4/16 (25)
3/16 (19)
1/16 (6)
No./Total No. (%)
Major and Fatal Bleeding DuringMajor and Fatal Bleeding DuringOral AnticoagulationOral Anticoagulation
• Finn et al, 1993
• 1% cumulative incidence of fatal bleeding at 1 year and 2% at 3 years
• Palareti et al, 1996
• 1.1% major bleeds/100 patient-years
• 0.25% fatal bleeds/100 patient-years
• Schulman et al, 1997
• 2.7% major hemorrhage in 6-month group compared with 8.6% in the indefinite treatment group
• Kearon et al, 1999
• 3.8% per patient-year incidence of major bleed in patients on therapy for 3 months
Low RiskModerate RiskHigh Risk
MI = myocardial infarction; DM = diabetes mellitus
Risk of BleedingRisk of Bleeding
Major Bleeding
2%5%
23%
3%12%48%
3 Months 12 Months(0)
(1 or 2)(3 or 4)
Age 65 yearsStroke in pastGastrointestinal bleeding in pastMI, anemia (Hct <30%), renal failure (Cr >1.5 mg/dL), or DM
Beyth et al, 1998
No. Risk Factors
Risk of Major Bleeding During Warfarin Risk of Major Bleeding During Warfarin AnticoagulationAnticoagulation
• < 65 years of age with no other risk factors:3%
65 years of age with multiple risk factors:42%
820 Patients Followed for 1 Year 820 Patients Followed for 1 Year
Beyth et al, 1998
Fatality Rates With Recurrent VTE Fatality Rates With Recurrent VTE and With Bleedingand With Bleeding
• 5% to 7% of recurrent PE events are fatal (Douketis et al, 1998).
• 20% of major bleeding events are fatal (Schulman et al, 1997; Palareti et al, 1996).
• Nonfatal recurrent VTE more serious than nonfatal major bleeding.
Duration of AnticoagulationDuration of Anticoagulation• VTE recurrences occur at a rate of 10%–25% in the first year
anticoagulants are discontinued. (Schulman 1995, Kearon 1998)
• Risk of recurrent VTE decreases over time, but risk of bleeding increases.
8.6%2.7%Major hemorrhage
2.6%20.7%Rate of VTE recurrence
Indefinite Treatment
6 Months of Therapy
Schulman 1997
Optimal Duration of Anticoagulant Therapy Optimal Duration of Anticoagulant Therapy for Symptomatic Venous Thrombosis: for Symptomatic Venous Thrombosis:
RecommendationsRecommendations
Indication Duration
Proximal thrombosis: reversible cause
Idiopathic proximal vein thrombosis
Idiopathic calf-vein thrombosis
Calf-vein thrombosis: reversible cause
3 to 6 months
6 months to >1 year
6 months to 1 year
6 weeks to 3 months
Factors That May Influence Duration Factors That May Influence Duration of Oral Anticoagulationof Oral Anticoagulation
Shorter Course• Bleeding risk• Unstable anticoagulant
response• Inconvenient anticoagulation• Fear of recurrence or
bleeding
Longer Course• VTE presentation (eg,
massive PE)• Poor cardiopulmonary
reserve• Severe post-thrombotic
syndrome• Thrombophilia• Recurrent VTE
Potential Indications for Indefinite Potential Indications for Indefinite Anticoagulant TherapyAnticoagulant Therapy
• Inherited thrombophilia: AT, protein C and S deficiency not factor V Leiden or prothrombin mutation
• Antiphospholipid syndrome
• Recurrent idiopathic VTE
• Malignancy
• Thromboembolic pulmonary hypertensionAT = antithrombin
Oral Small-Molecule Oral Small-Molecule Direct Thrombin Inhibitor*Direct Thrombin Inhibitor*
• Direct comparison with warfarin currently in progress
• If oral small-molecule direct thrombin inhibitor is as effective as warfarin, the advantages will be as follows:
– No monitoring
– Fewer drug interactions
* The new oral small-molecule direct thrombin inhibitor does not have FDA approval for any indication.
Thrombolytic TherapyThrombolytic Therapy
DVT• Thrombolytic therapy achieves complete early lysis in
30% to 40% of cases (heparin 10%).
• Increases bleeding threefold.
• Probably reduces the incidence of post-thrombotic syndrome. However, risk of severe post-thrombotic syndrome about 10% with adequate anticoagulation.
• Catheter-directed thrombolysis with administration into thrombus claimed to be more effective, but further study is required.
Thrombolytic TherapyThrombolytic Therapy
PE• Two-hour high-dose t-PA or urokinase effective.
• Improves resolution at 24 hours but not at 7 days.
• Role in massive embolism accepted.
• Role in submassive, major embolism controversial.
Thrombolysis(n=188)
38%
Thrombolysis for DVTThrombolysis for DVT
45% 13%
No Change Marked LysisMajor
Bleeding
Hirsh et al, 1996
• Pooled analysis of eight randomized trials
Repeat Venography
Heparin(n=144)
78% 10% 3.5%
Thrombolysis 12%
Thrombolysis for PEThrombolysis for PE
30% 58%
2 hours 1 day 1 month
Dalen et al, 1997
Improvement of Perfusion
Heparin 0% 10% 60%
45%
1 week
40%
• Accelerates resolution• No effect on extent of resolution• No effect on frequency of recurrence
Classification of Acute PEClassification of Acute PE
• Massive PE with shock or syncope
• Major PE with right-ventricular dysfunction
• Major PE with normal right-ventricular function
• Minor PE
Goldhaber, 1999Nass et al, 1999
Recommended Treatment of Acute PERecommended Treatment of Acute PE
• Massive PE with shock or syncope– Thrombolysis or surgery
• Major PE with right-ventricular dysfunction– Anticoagulants (Dalen)– Thrombolysis (Goldhaber)
• Major PE without right-ventricular dysfunction– Anticoagulants
• Minor PE– Anticoagulants
Hyers et al, 1998Goldhaber, 1999Goldhaber, 1998
Dalen et al, 1997Nass et al, 1999
Thrombolysis for Massive PEThrombolysis for Massive PE
Heparin (10,000 U bolus + 1000 U/hr IV) versus streptokinase (1.5 million U IV over 60 min) + heparin
Patients (8)• Cardiogenic shock; HR 124; Pa02 46 (4/4 heparin patients had already deteriorated on heparin)
Heparin Streptokinase + HeparinMortality 4/4 0/4
Jerjes-Sanchez et al, 1995
Randomized Trial of Alteplase versus Randomized Trial of Alteplase versus Heparin in Normotensive Patients Heparin in Normotensive Patients
With Acute PEWith Acute PE
Recurrent PE
Death
Heparin(n=55)
5 (9%)
Alteplase(n=46)
0
P
0.06
All events occurred in patients with right-ventricular dysfunction.
2 (3.6%) 0
Goldhaber et al, 1993
Management Strategy and Prognosis Management Strategy and Prognosis for Pulmonary Embolism (MAPPET)for Pulmonary Embolism (MAPPET)
Konstantinides et al, 1997
• 719 patients without cardiogenic shock
• 169 received thrombolytic therapy:30-day mortality 4.7%; recurrent PE 7.7%; major bleeding 21.9%
• 550 received heparin:30-day mortality 11.1%; recurrent PE 18.7%; major bleeding 7.8%
Heparin or Thrombolysis in Heparin or Thrombolysis in Hemodynamically Stable Major Acute Hemodynamically Stable Major Acute PE With Right-Ventricular DysfunctionPE With Right-Ventricular Dysfunction
PE recurrence %
Bleeding %SevereIntracranial
Death %
Thrombolysis(n=64)
15.6
4.7
Heparin(n=64)
0
0
P
0.001
0.24
128 consecutive patients (matched but not randomized) between 1992 and 1997
Hamel et al, 1998
9.4 0 0.028
6.25 0 0.12
4.7 4.7 1.0
Pulmonary EmbolectomyPulmonary Embolectomy
• Can be life saving in patients with massive PE.
• In consecutive series of 96 patients, mortality was 37% (Meyer et al, 1991).
• Cardiac arrest and associated cardiopulmonary disease were independent predictors of death.
• Elective pulmonary embolectomy was life saving in selected patients with chronic thromboembolic pulmonary hypertension (Moser et al, 1990).
Randomized Trial of Caval InterruptionRandomized Trial of Caval Interruption
• Initial benefit in preventing PE offset by excess of recurrent DVT in the longer term in the absence of anticoagulant.
• Therefore, caval filter not recommended for this patient population in the long term.
Decousus et al, 1998
Evaluation of Inferior Venacaval Filter in Evaluation of Inferior Venacaval Filter in Patients With Proximal Venous ThrombosisPatients With Proximal Venous Thrombosis
Symptomatic PE at day 12Total PE at day 12
Recurrent DVT at 2 years
IVC Filter
2
37 (20.8%)
No Filter
5
21 (11.6%)†
2 (1.1%)
9 (4.8%)*
All patients received 3 months of anticoagulants; primary end-point data unavailable for 28 patients.
*P=0.03 †P=0.02
Decousus et al, 1998
Treatment of VTETreatment of VTE
• Anticoagulants
• Thrombolytic Therapy
• Caval Interruption
• Surgical Removal
Issues for Future ResearchIssues for Future Research
• Optimal duration of anticoagulant therapy
• Lower therapeutic range for warfarin
• Relative efficacy and safety of new oral small-molecule direct thrombin inhibitor* versus warfarin
• Role of thrombolytic therapy for treatment of DVT and PE
* The new oral small-molecule direct thrombin inhibitor does not have FDA approval for any indication.